The present invention relates to a pharmaceutically useful novel heterocyclic derivative or a salt thereof, and a pharmaceutical composition containing the same as an active ingredient.
As an analgesic, a narcotic analgesic (such as morphine), a non-narcotic analgesic (such as aspirin or indomethacin) or a narco-antagonistic analgesic (such as pentazocine) is employed. A narcotic analgesic exerts its analgesic effect mainly by inhibiting a central algesic excitatory transmission. A non-narcotic analgesic exerts its analgesic effect mainly by inhibiting the production of a peripheral dolorogenic substance. A narco-antagonistic analgesic exerts its analgesic effect in a mechanism similar to that of a narcotic analgesic.
However, there is no analgesic which is effective against a chronic pain which is not suppressed by morphine, an allodynia accompanied with herpes zoster or hyperalgesia, and an excellent analgesic has been desired to be created.
Nociceptin is a neuropeptide related to various nervous activities including an in vivo algesia. Japanese Unexamined Patent Publication No. 10-212290 describes that a nociceptin agonist and/or antagonist may be effective in treating a mental disorder, neuropathy and physiological disorder, and particularly effective in ameliorating anxiety and stress disorder, depression, traumatic disorder, amnesia due to Alzheimer""s disease or other dementia, symptoms of epilepsy and spasm, acute and/or chronic pain, drug abuse withdrawal symptoms, water balance control, Na+ excretion, arterial blood pressure disorder, and eating disorder such as an obesity.
As a non-peptide compound acting on a nociceptin receptor, lofentanil, naloxone benzoylhydrazone and 2-oxoimidazole derivative (International Publication WO9854168) are known. However, these compounds are still at the stage of a basic research, and none of them has been commercially available.
As a compound analogous to a quinazoline derivative in the heterocyclic derivatives of the compound according to the present invention, various compounds were known (International Publication WO9307124, Japanese Examined Patent Publication No. 2923742, International Publication WO9720821, International Publication WO9850370, International Publication WO9909986, Japanese Unexamined Patent Publication No. 47-2927, International Publication WO9817267 and the like). Among these, International Publication WO9720821 describes that a 2-acylaminoquinazoline derivative has an inhibitory effect on a neuropeptide Y (NPY) receptor subtype-Y5 and is effective in ameliorating an algesia or amnesia.
An object of the present invention is to provide a novel compound having an excellent analgesic effect. More particularly, the present invention is intended to provide a novel analgesic having an analgesic effect which is effective widely against a chronic pain or an allodynia accompanied with herpes zoster by acting on a nociceptin receptor.
In order to achieve the above described objects, the present inventors found that compound represented by the following general formula (1) is an agonist and/or antagonist of a nociceptin receptor and has an excellent analgesic effect in processes to synthesize and study various compounds, thereby establishing the present invention.
Accordingly, the present invention relates to a compound represented by the following general formula (1): 
or a salt thereof.
In the formula, X and Y are same or different and each represents a nitrogen atom or CH;
R1 represents a hydrogen atom or alkyl;
A1 and A2 are same or different and each represents (1) a single bond or (2) a divalent aliphatic hydrocarbon group which may be substituted and which may include 1 to 3 unsaturated bonds at any positions (such aliphatic hydrocarbon group may contain one heteroatom selected from a group consisting of xe2x80x94NHxe2x80x94, O and S);
Q represents (1) a single bond, (2) an optionally substituted 3- to 8-membered cycloalkylene group, (3) an optionally substituted phenylene group or (4) an optionally substituted 4- to 8-membered divalent heterocyclic group;
R2A, R2C and R2D are same or different and each represents a hydrogen atom, alkyl or phenyl, R2B represents a hydrogen atom, alkyl, cyano, nitro or phenyl, or a two nitrogen atoms of a guanidino group are cyclized together with one or two of its substituents R2B, R2C and R2D to form a saturated or unsaturated 5- or 6-membered ring;
or is taken together as xe2x80x94N(R1)xe2x80x94A1xe2x80x94Q-A2xe2x80x94N(R2A)xe2x80x94 to form a 5- to 7-membered ring;
E represents (1) ethenylene, (2) xe2x80x94NRCOxe2x80x94, (3) xe2x80x94NRCONHxe2x80x94, (4) xe2x80x94CONRxe2x80x94, (5) ethynylene, (6) xe2x80x94NRSO2xe2x80x94 or (7) aminoalkylene (in which R represents hydrogen or optionally substituted alkyl);
R3 represents an optionally substituted phenyl group or heterocyclic group;
R4 and R5 (1) are same or different and each represents a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen, nitro, hydroxy, alkoxycarbonyl, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6SO2R7, xe2x80x94CONR6R7 (in which R6 and R7 are same or different and each represents a hydrogen atom or alkyl) or (2) when adjacent to each other are taken together to form xe2x80x94O(CH2)nOxe2x80x94 (wherein n is an integer of 1 or 2) or xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94.
Preferably, in the formula (1), each of X and Y represents a nitrogen atom or CH;
R1 represents a hydrogen atom or alkyl;
A1 and A2 are same or different and each represents (1) a single bond or (2) alkylene which may be substituted by alkyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, hydroxy, alkoxy or trifluoromethyl and which may have 1 to 3 unsaturated bonds at any positions;
Q represents (1) a single bond, (2) a 3- to 8-membered cycloalkylene group which may be substituted by alkyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or alkoxy, (3) a phenylene group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, amino, monoalkylamino, dialkylamino, nitro, halogen, cyano or trifluoromethyl, or (4) a 4- to 8-membered divalent heterocyclic group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, amino, monoaklylamino or dialkylamino;
R2A, R2C and R2D are same or different and each represents a hydrogen atom, alkyl or phenyl, R2B represents a hydrogen atom, alkyl, cyano group, nitro group or phenyl, or a two nitrogen atoms of a guanidino group are cyclized together with one or two of its substituents R2B, R2C and R2D to form a saturated or unsaturated 5- or 6-membered ring;
or is taken together as xe2x80x94N(R1)xe2x80x94A1xe2x80x94Qxe2x80x94A2xe2x80x94N(R2A)xe2x80x94 to form a 5- to 7-membered ring;
E represents (1) ethenylene, (2) xe2x80x94NRCOxe2x80x94, (3) xe2x80x94NRCONHxe2x80x94, (4) xe2x80x94CONRxe2x80x94, (5) ethynylene, (6) xe2x80x94NRSO2xe2x80x94 or (7) aminoalkylene (in which R represents hydrogen or optionally substituted alkyl);
R3 represents a phenyl group or heterocyclic group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkylsulfonylamino, N-(alkyl)alkylsulfonylamino, amino, monoalkylamino, dialkylamino, nitro, halogen, cyano, hydroxy or trifluoromethyl; and
R4 and R5 (1) are same or different and each represents a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen, nitro, hydroxy, alkoxycarbonyl, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6SO2R7, xe2x80x94CONR6R7 (in which R6 and R7 are same or different and each represents a hydrogen atom or alkyl) or (2) when adjacent to each other are taken together to form xe2x80x94O(CH2)nOxe2x80x94 (wherein n represents an integer of 1 or 2) or xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94.
A more preferable compound is represented by the general formula (1), wherein each of X and Y is a nitrogen atom, R1 is a hydrogen atom or alkyl, A1 and A2 are same or different and each is (1) a single bond or (2) optionally substituted alkylene, Q is (1) a single bond, (2) an optionally substituted 4- to 8-membered cycloalkylene group (3) an optionally substituted phenylene group or (4) an optionally substituted 5- to 7-membered divalent heterocyclic group, R2A, R2B, R2C and R2D are same or different and each is a hydrogen atom, alkyl or phenyl, or taken together as xe2x80x94N(R1)xe2x80x94A1xe2x80x94Qxe2x80x94A2xe2x80x94N(R2A)xe2x80x94 to form a 5- to 7-membered ring, E is (1) ethenylene, (2) xe2x80x94NRCOxe2x80x94 or (3) xe2x80x94CONRxe2x80x94, and R4 and R5 (1) are same or different and each represents a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen, nitro, hydroxy or alkoxycarbonyl or (2) when adjacent to each other are taken together to form xe2x80x94O(CH2)nOxe2x80x94 (wherein n is an integer of 1 or 2) or xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94.
A further preferable compound is represented by the general formula (1), wherein each of X and Y is a nitrogen atom, R1 is a hydrogen atom, A1 and A2 are same or different and each is (1) a single bond or (2) optionally substituted alkylene, Q is (1) a single bond, (2) an optionally substituted 5- to 7-membered cycloalkylene group or (3) an optionally substituted phenylene group, R2A, R2B, R2C and R2D are same or different and each is a hydrogen atom, alkyl or phenyl, E is (1) ethenylene or (2) xe2x80x94NRCOxe2x80x94, and R4 and R5 are same or different and each is a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen or nitro.
The present invention further relates to a pharmaceutical composition including any of those compounds mentioned above or a salt thereof, and more particularly to an analgesic.
A structual feature of a compound of the present invention is as follows: the presence of a guanidino group at the end of the substituent, xe2x80x94N(R1)xe2x80x94A1xe2x80x94Qxe2x80x94A2xe2x80x94, in the 4-position of a quinazoline or quinoline skeleton or 1-position of the isoquinoline skeleton; or the cyclization of two NHs in the ganidino group together with a substituent thereon.
A compound according to the present invention, which has the feature described above, is a novel compound which was not found in references. A compound according to the present invention acts on a nociceptin receptor thereby exerting an excellent analgesic effect.
The present invention will be detailed below.
Examples of an xe2x80x9calkylxe2x80x9d in the present invention may include a straight or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 5-isopentyl, n-hexyl, isohexyl and the like. Particularly, alkyl having 1 to 4 carbon atoms is preferable.
Examples of xe2x80x9calkoxyxe2x80x9d may include a straight or branched alkoxy having 1 to 6 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like. Particularly, alkoxy having 1 to 4 carbon atoms is preferable.
Examples of xe2x80x9caralkyloxyxe2x80x9d may include aralkyloxy having 7 to 10 carbon atoms, for example, benzyloxy, phenetyloxy and the like. Particularly, benzyloxy is preferable.
Examples of a xe2x80x9cdivalent aliphatic hydrocarbon groupxe2x80x9d may include a straight or branched alkylene having 1 to 6 carbon atoms (for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethyltrimethylene and 1-methyltetramethylene), a straight or branched alkenylene having 2 to 6 carbon atoms (for example, vinylene and propenylene) or a straight or branched alkynylene having 2 to 6 carbon atoms (for example, ethynylene). Such an aliphatic hydrocarbon group may contain one heteroatom selected from a group consisting of NH, oxygen atom and sulfur atom.
Examples of the alkylene in an xe2x80x9caminoalkylenexe2x80x9d may include an alkylene listed in the xe2x80x9cdivalent aliphatic hydrocarbon groupxe2x80x9d.
Examples of a xe2x80x9ccycloalkylenexe2x80x9d may include cycloalkylene having 3 to 8 carbon atoms, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and cyclooctylene. Such a cycloalkylene may have 1 to 2 substituents, and an example of such substituents may include alkyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or alkoxy. It may also contain an unsaturated bond, and examples of cycloalkylene containing such an unsaturated bond include cyclohexenylene, cycloheptenylene, cyclooctenylene and the like.
Examples of a xe2x80x9chalogenxe2x80x9d may include fluorine, chlorine, bromine and iodine atoms.
Examples of a heterocyclic ring in a xe2x80x9cheterocyclic groupxe2x80x9d and xe2x80x9cdivalent heterocyclic groupxe2x80x9d may include a 4-to 8-membered monocyclic or fused ring which contains 1 to 2 heteroatoms selected from a group consisting of NH, oxygen atom and sulfur atom, and which may have 1 to 4 unsaturated bonds. Examples of R3 may include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinolyl, 2-pyrazinyl and 3-pyrazinyl. Such a heterocyclic group may have 1 to 2 substituents, and examples of the substituents may include alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkylsulfonylamino, N-(alkyl)alkylsulfonylamino, amino, monoalkylamino, dialkylamino, nitro, halogen, cyano, hydroxy or trifluoromethoxy. Examples of a heterocyclic ring in a heterocyclic group Q may include pyridine, pyrimidine, piperazine, homopiperazine, furan, thiophene and the like. The heterocyclic group Q may have 1 to 2 substituents, and examples of such substituents may include alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, amino, monoalkylamino or dialkylamino.
A xe2x80x9cphenylene groupxe2x80x9d may have 1 to 2 substituents, and examples of such substituents may include alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, amino, monoalkylamino, dialkylamino, hydroxy, nitro, halogen, cyano and trifluoromethyl.
An example of a ring represented by xe2x80x94N(R1)xe2x80x94A1xe2x80x94Qxe2x80x94A2xe2x80x94N(R2A)xe2x80x94 may include a 5- to 7-membered saturated ring, such as piperazino or homopiperazino.
Examples of a xe2x80x9csaltxe2x80x9d of the compound (1) encompassed in the present invention may include a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid or hydrobromic acid, or a salt with an organic acid such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or camphorsulfonic acid.
Examples of a particularly preferred compound may include (1S,2R)-N-amidino-2-{[2-(4-chlorobenzoylamino)-6-methoxyquinazolin-4-yl]amino}cyclohexylamine dihydrochloride, N-amidino-2-[6-methoxy-4-{2-[2-(2-pyridyl)ethenyl]quinazolin-4-yl}aminoethyl]phenylethylamine trihydrochloride, cis-4-guanidinomethyl-cis-2-methyl-N-{6-methoxy-2-[2-(2-pyridyl)ethenyl]quinazolin-4-yl}cyclohexylamine trihydrochloride, N-amidino-Nxe2x80x2-{6-methyl-2-[2-(2-pyridyl)ethenyl]quinazolin-4-yl}-1,6-hexanediamine trihydrochloride, (1S,2R)-cis-N-amidino-2-{[2-(4-chlorostyryl)-6-methoxyquinazolin-4-yl]amino}cyclohexylamine dihydrochloride and N-amidino-Nxe2x80x2-{6-methoxy-2-[2-(2-pyridyl)ethenyl]quinazolin-4-yl}-1,6-hexanediamine trihydrochloride.
A compound according to the present invention may exist as a cis (Z form) isomer or a trans (E form) isomer, and each isomer and a mixture thereof are also included in the present invention.
Some of the compounds according to the present invention may have asymmetric carbon atoms, and each optical isomer and a racemate thereof are also included in the present invention. An optical isomer can be produced, for example, by starting from a racemate obtained as described above utilizing the basic property thereof using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid and the like) by a known method to effect an optical resolution, or by starting from a previously prepared optically active compound.
The compound (1) according to the present invention can be produced, for example, by the following methods.
Production Method A 
(wherein X, Y, R1, R2A, R2B, R2C, R2D, R3, R4, R5, A1, A2, Q and E are the same meanings as described above. R2b and R2c are same or different and each represents a hydrogen atom, alkyl, phenyl, cyano, nitro or a protective group. L represents a leaving group.)
Examples of a protective group may include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl and the like. Examples of a leaving group may include pyrazol-1-yl, methylthio, methoxy, halogen and the like. A compound (2) is reacted with one equivalent to excess amount of a compound (3) in hydrocarbons such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated-hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane or in N,N-dimethylformamide at a temperature from 0xc2x0 C. to the boiling point of the employed solvent for several hours to several days followed by deprotecting R2b and R2c, when being present as protective groups, by a method known per se, thereby obtaining the compound (1). It is preferred particularly to employ pyrazol-1-yl as a leaving group L on the compound (3) and tert-butoxycarbonyl as a protective group, 1,2-dichloroethane as a solvent, and to effect the reaction at room temperature for 1 to 48 hours followed by the deprotection with hydrochloric acid.
Production Method B (When R2B in the Compound (1) is a Hydrogen Atom) 
(wherein X, Y, R1, R2A, R2B, R2C, R2D, R3, R4, R5, A1, A2, Q and E are the same meanings as described above.)
A compound (1a) can be produced by reacting the compound (2) with R2CR2DNxe2x80x94CN by a known method (J. Med. Chem. 18, 90, 1975 and the like).
Production Method C (When R2D in the Compound (1) is a Hydrogen Atom) 
(wherein X, Y, R1, R2A, R2B, R2C, R3, R4, R5, A1, A2, Q and E are the same meanings as described above.)
The compound (1b) can be produced by reacting the compound (2) with R2Bxe2x80x94Nxe2x95x90Cxe2x95x90Nxe2x80x94R2C by a known method (J. Am. Chem. Soc., 3673, 1962 and the like).
Production Method D 
(wherein X, Y, R1, R2A, R2B, R2C, R2D, R3, R4, R5, A1, A2, Q and E are the same meanings as described above. R8 represents an alkyl.)
The compound (1) can be produced from a compound (120) by a known method (Synthesis, 6, 460, 1988 and the like). An alkyl as R8 is an alkyl having 1 to 4 carbon atoms, and is preferably methyl.
Production Method E
A compound (1A) which is the compound (1) wherein E is ethenylene, X and Y are both N can be produced by the reaction process shown below. 
(wherein R1, R2A, R2B, R2C, R2D, R3, R4, R5, A1, A2, R2b, R2c and Q are the same meanings as described above.)
A compound (13) is reacted with one equivalent to excess amount of an amine (4) in the presence of a base such as sodium hydride or N,N-diisopropylethylamine in a solvent having a high boiling point such as 1-pentanol, N,N-dimethylformamide or phenol, at a temperature from 50xc2x0 C. to the boiling point of the employed solvent for several hours to several days followed by deprotecting R2b and R2c, when being present as protective groups, by a method known per se, thereby obtaining the compound (1A). Preferably, the reeaction is carried out in phenol at 150xc2x0 C. to 180xc2x0 C. for 5 to 24 hours followed by deprotection using hydrochloric acid to obtain the compound (1A).
Production Method F
A compound (1Z) which is the compound (1) wherein E is xe2x80x94NRCOxe2x80x94 and X and Y are both N can be produced also by the reaction process shown below. 
(wherein R, R1, R2A, R2B, R2C, R2D, R3, R4, R5, A1, A2, R2b, R2c and Q are the same meanings as described above.)
A compound (37B) is reacted with one equivalent to excess amount of the compound (3) in hydrocarbons such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated-hydrocarbones such as chloroform, methylene chloride and 1,2-dichloroethane or in N,N-dimethylformamide at a temperature from 0xc2x0 C. to the boiling point of the employed solvent for several hours to several days, thereby obtaining a compound (37A). It is preferred particularly to employ pyrazol-1-yl as a leaving group L on the compound (3) and tert-butoxycarbonyl as a protective group, 1,2-dichloroethane as a solvent.
The compound (37A) is reacted with one equivalent to excess amount of an acid chloride in hydrocarbons such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated-hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform in the presence of a base such as triethylamine, N,N-diisopropylethylamine or pyridine if necessary using a catalyst such as 4-dimethylaminopyridine at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days followed by deprotecting R2b and R2c, when being present as protective groups, by a method known per se, thereby obtaining the compound (1Z).
The compound (1) thus produced can be isolated and purified by a method known per se, such as concentration, liquid phase conversion, partition, solvent extraction, crystallization, recrystallization, fractional distillation or chromatography.
A starting compound (2) can be produced in accordance with the following reaction scheme.
(a) When E is Ethenylene and X and Y are Both N in the Compound (2) 
(wherein R1, R2A, R3, R4, R5, A1, A2 and Q are the same meanings as described above. P1 represents a protective group.)
Examples of a protective group may include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
A compound (13) (obtained similarly to in page 13 to 15 in International Publication WO9909986) is reacted with one equivalent to excess amount of an amine (14) in hydrocarbons such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, alcohols such as ethanol and isopropanol, or in an organic solvent such as N,N-dimethylformamide, if necessary in the presence of a base such as triethylamine or N,N-diisopropylethylamine, at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days followed by deprotection with hydrochloric acid, trifluoroacetic acid or by hydrogenation with palladium/carbon, thereby obtaining a compound (2A). It is preferred particularly that the compound (13) is reacted with 1 to 2 equivalents of an amine (14) wherein P1 is tert-butoxycarbonyl in toluene as a solvent in the presence of triethylamine (TEA) at 100xc2x0 C. to 130xc2x0 C. for 24 to 48 hours and then deprotection is effected with hydrochloric acid.
(b) When E is Ethenylene, X is CH, Y is N in the Compound (2) 
(wherein R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above.)
Starting from a compound (16), a known method (see JACS 70, 4065 (1948); JACS 70, 2402 (1948); JOC 12, 456 (1947) and the like) is employed to produce a compound (19).
The compound (19) is reacted with an aldehyde (11) in a solvent such as acetic anhydride, acetic acid or trifluoroacetic acid at a temperature from room temperature to the boiling point of the employed solvent for 1 to 48 hours, preferably in acetic anhydride as a solvent at 80xc2x0 C. to 100xc2x0 C. for 5 to 24 hours, thereby obtaining a compound (20). The aldehyde (11) may be commercially available or can be produced by a known method.
The compound (20) is reacted with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride without using any solvent or in a solvent such as toluene, xylene or 1,2-dichloroethane at a temperature from room temperature to the boiling point of the employed solvent, or a temperature from room temperature to the boiling point of the chlorinating agent employed in case where no solvent is used, for 1 to 24 hours, thereby obtaining a compound (21). In this procedure, a tertiary amine such as dimethylaniline or triethylamine may be present if necessary.
The compound (21) is reacted with one equivalent to excess amount of the amine (14) in the above-described (a), and then deprotected if necessary by a method known per se to obtain a compound (2B). It is preferred particularly that the compound (21) is reacted with 1 to 2 equivalents of the amine (14) wherein P1 is tert-butoxycarbonyl in toluene as a solvent in the presence of triethylamine at 100xc2x0 C. to 130xc2x0 C. for 24 to 48 hours to obtain a compound (22) which is then deprotected with trifluoroacetic acid in methylene chloride.
(c) When E is Ethenylene, X is N and Y is CH in the Compound (2) 
(wherein R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above.)
Starting from a compound (23), a known method (J. Chem. Soc. Perkin Trans 1, 1990, 1770) is employed to produce a compound (24).
The compound (24) is reacted with 1 to 3 equivalents of selenium dioxide in ethers such as dioxane and tetrahydrofuran, or alcohols such as ethanol and isopropanol at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days, preferably in dioxane at 50xc2x0 C. to 100xc2x0 C. for 5 to 48 hours, thereby obtaining a compound (25).
The compound (25) is reacted with a compound (26) or a compound (27) in a solvent which does not participate in the reaction such as dioxane or tetrahydrofuran, in the presence of a base such as n-butyllithium, sodium hydride or sodium hexamethyl disilazide at a temperature from xe2x88x9278xc2x0 C. to the boiling point of the employed solvent for several hours to several days, preferably in tetrahydrofuran at a temperature from xe2x88x9220xc2x0 C. to room temperature for 1 to 5 hours, thereby obtaining a compound (28).
Similarly to the procedure in the above-described (b), the compound (28) is reacted with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride for 1 to 24 hours to obtain a compound (29). The compound (29) is reacted with one equivalent to excess amount of the amine (14) in the above-described (a) and then deprotected if necessary by a method known per se to obtain a compound (2C).
(d) When E is xe2x80x94NRCOxe2x80x94 and X and Y are Both N in the Compound (2) 
(wherein R, R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above. X represents a hydroxy group or amino group. P2 represents a hydrogen atom or a protective group such as benzyl or 4-methoxybenzyl).
A compound (34) can be produced from the compounds (31) and (32) in accordance with a known method (Japanese Patent No. 2923742).
The compound (34) is reacted with one equivalent to excess amount of the amine (14) in the same solvent as that of the above-described (a) if necessary in the presence of a base such as triethylamine or N,N-diisopropylethylamine at a temperature from 0xc2x0 C. to the boiling point of the employed solvent for several hours to several days, preferably in the presence of triethylamine at room temperature for 5 to 48 hours to obtain a compound (35).
The compound (35) is reacted with one equivalent to excess amount of an amine (36) in a solvent having a high boiling point such as phenol or diphenyl ether, if necessary in the presence of a base such as triethylamine or N,N-diisopropylethylamine at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days, or in hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and tetrahydrofuran, in the presence of a metal catalyst such as palladium acetate, a ligand such as 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl and a base such as sodium tert-butoxide at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days, and followed by deprotecting P2 when being present as a protective group by a method having no effect on P1, whereby obtaining a compound (37).
The compound (37) is reacted with one equivalent to excess amount of an acid chloride in hydrocarbons such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform in the presence of a base such as triethylamine, N,N-diisopropylethylamine or pyridine if necessary using a catalyst such as 4-dimethylaminopyridine at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days, thereby obtaining a compound (38). The compound (38) is deprotected by a method known per se to obtain a compound (2D). It is preferred particularly to effect the reaction using methylene chloride as a solvent in the presence of triethylamine using a catalytic amount of 4-dimethylaminopyridine at room temperature for 24 to 48 hours. The acid chloride may be commercially available or can be produced by a known method.
(e) When E is xe2x80x94NHCOxe2x80x94 and X and Y are Both N in the Compound (2) 
(wherein R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above.)
Starting from a compound (39), a known method (see JOC 27, 4672 (1962)) is employed to obtain a compound (41).
The compound (41) is reacted with one equivalent to excess amount of the amine (14) as similar to the above-described (a) to obtain a compound (42). It is preferred particularly to react the compound (41) with 1 to 2 equivalents of the amine (14) in toluene as a solvent in the presence of triethylamine (TEA) at 100xc2x0 C. to 130xc2x0 C. for 24 to 48 hours.
By hydrolyzing the compound (42) by a method known per se, a compound (43) is obtained. It is preferred particularly to react the compound (42) in ethanol in the presence of a 1N aqueous solution of sodium hydroxide at room temperature to 60xc2x0 C. for 1 to 3 hours.
The compound (43) is reacted with diphenylphosphoryl azide (DPPA) in alcohols such as ethanol and benzyl alcohol in the presence of a base such as triethylamine or N,N-diisopropylethylamine at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days, thereby obtaining a compound (44). It is preferred particularly to react the compound (43) in a refluxing ethanol in the presence of triethylamine for 24 to 48 hours.
The compound (44) is hydrolyzed by a method known per se which has no effect on P1, thereby obtaining a compound (45). It is preferred particularly to react the compound (44) in methanol in the presence of potassium hydroxide at room temperature to 60xc2x0 C. for 1 to 3 hours.
The compound (45) is reacted with one equivalent to excess amount of an acid chloride in hydrocarbons such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated-hydrocarbons such as methylene chloride and 1,2-dichloroethane in the presence of a base such as triethylamine, N,N-diisopropylethylamine or pyridine if necessary using a catalyst such as 4-dimethylaminopyridine at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days, thereby obtaining a compound (46). It is preferred particularly to effect the reaction using methylene chloride as a solvent in the presence of triethylamine using a catalytic amount of 4-dimethylaminopyridine at room temperature for 24 to 48 hours.
The compound (46) is deprotected by a method known per se to obtain a compound (2E). When P1 is tert-butoxycarbonyl, it is preferred to react trifluoroacetic acid in methylene chloride at room temperature for 1 to 5 hours. When P1 is benzyloxycarbonyl, it is preferred to effect hydrogenation in methanol in the presence of 5% palladium/carbon at room temperature under atmospheric pressure.
(f) When E is Ethynylene and X and Y are Both N in the Compoumd (2) 
(wherein R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above.)
Starting from the compound (35), a known method (see Heterocycles 24, 2311 (1986) and the like) is employed to obtain a compound (200). The compound (200) is deprotected by a method known per se to obtain a compound (2F).
(g) When E is xe2x80x94CONRxe2x80x94 and X and Y are Both N in the Compound (2) 
(wherein R, R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above.)
Starting from the compound (43), an amidation method known per se is employed to produce a compound (210). The compound (210) is then deprotected by a method per se to obtain a compound (2G).
(h) When E is xe2x80x94NRSO2xe2x80x94 and X and Y are Both N in the Compound (2) 
(wherein R, R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above.)
Starting from the compound (45) and in accordance with a sulfonamidation method known per se, a compound (220) can be produced. The compound (220) is then deprotected by a method known per se to obtain a compound (2H).
(i) When E is xe2x80x94NRCONHxe2x80x94 and X and Y are Both N in the Compound (2) 
(wherein R, R1, R2A, R3, R4, R5, A1, A2, Q and P1 are the same meanings as described above.)
Starting from the compound (45), an isocyanate is reacted by a method known per se to produce a compound (230). The compound (230) is then deprotected by a method known per se to obtain a compound (2I).
A starting compound (3) can be produced in accordance with a known method (J. Org. Chem. 34, 616, 1969; Synthesis 6, 460, 1988 and the like).
A starting compound (4) can be produced in accordance with the following reaction scheme. 
(wherein R1, R2A, R2b, R2c, R2D, A1, A2, Q, L and P1 are the same meanings as described above.)
The compound (100) is reacted similarly to Production Method A described above to obtain the starting compound (4). This starting compound (100) may be commercially available or can be produced by a method known per se.
A starting compound (120) can be produced in accordance with the following reaction scheme. 
(wherein R1, R2A, R2B, R3, R4, R5, A1, A2, E, Q, X and Y are the same meanings as described above.)
A compound (110) is reacted with one equivalent to excess amount of R2BNxe2x95x90Cxe2x95x90S in a solvent similar to that in Production Method A described above if necessary in the presence of a base such as triethylamine or N,N-diisopropylethylamine at a temperature from room temperature to the boiling point of the employed solvent for several hours to several days to obtain the starting compound (120). It is preferred particularly to react in methylene chloride at room temperature for 1 to 24 hours.
In a production method described above, an amino group or hydroxyl group may be protected if necessary by a protective group employed conventionally, and after being subjected to the reaction it can be deprotected at an appropriate stage by a method known per se such as treatment with an acid or alkali or by catalytic hydrogenation. Examples of an amino protective group may include benzyl, benzyloxycarbonyl, t-butoxycarbonyl and trifluoroacetyl. Examples of a hydroxyl protective group may include methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl and the like.
A salt of the compound (1) of the present invention can be produced by a method known per se. For example, a hydrochloride of the compound (1) of the present invention can be obtained by treating the compound (1) of the present invention with a solution of hydrogen chloride in an alcohol or ethyl ether followed by recovering the precipitated crystals by filtration, or, in case where no crystal is precipitated, by concentrating the solution to precipitate crystals which are then recovered by filtration.
Since a compound according to the present invention represented by the formula (1) binds to a nociceptin receptor as shown in Test Examples described later to exert an agonist or antagonistic effect, it is useful as an analgesic, anti-inflammatory agent, diuretic, anesthetic, anti-hypertensive agent, anti-anxiety agent, anti-obesity agent, auditory controller, anti-depressant, anti-dementia agent, narcotic analgesic resistance-overcoming agent.
When an compound of the present invention is administered as a medicament, it can be administered to a mammal including human as it is or in a mixture with a pharmaceutically acceptable non-toxic inert carrier, for example, as a pharmaceutical composition containing the compound at a level of 0.1% to 99.5%, preferably 0.5% to 90%.
As a carrier, one or more of auxiliary agents for a formulation such as solid, semi-solid and liquid diluent, filler and other auxiliary agents for a drug formulation may be used. It is desirable that a pharmaceutical composition is administered as a unit dosage form. Since a compound of the present invention is water-soluble, it can be employed not only in a solid formulation but also in a liquid formulation (e.g., intravenous injection formulation, bladder infusion, oral syrup). The pharmaceutical composition can be administered into tissue, or orally, topically (percutaneously) or rectally. It is a matter of course that a dosage form suitable for any of the administration modes described above is employed. For example, oral or intravenous administration is preferable.
While it is desirable that the dose as an analgesic may be adjusted depending on the conditions of the patients including the age, body weight, nature and degree of the pain as well as the administration route, a daily dose as an active ingredient in an adult is usually 1 mg to 1000 mg per adult, preferably 1 mg to 500 mg per adult when given orally, and usually 1 mg to 100 mg per adult, preferably 1 mg to 50 mg per adult when given intravenously. In some cases, a lower dose may be sufficient or a higher dose may be required. Usually, the dose is given once or several times as being divided into portions, or given intravenously and continuously over a period of 1 to 24 hours a day.
The administration into a tissue can be accomplished by using a liquid unit dosage form, for example in the form of a solution or suspension, of a subcutaneous, intramuscular, bladder or intravenous injection formulation. Any of these formulations can be produced by suspending or dissolving a certain amount of a compound in a non-toxic liquid carrier such as an aqueous or oily medium compatible with the purpose of the injection followed by sterilizing said suspension or solution. Alternatively, a certain amount of a compound is placed in a vial, which is then sterilized together with its content and then sealed. For reconstitution or mixing just before use, a powdery or freeze-dried active ingredient is provided with a complementary vial or carrier. It is also possible to add a non-toxic salt or salt solution for the purpose of making an injection solution isotonic. It is also possible to use a stabilizer, preservative, emulsifier and the like.
Oral administration can be accomplished in a solid or liquid dosage form, such as a particle, powder, tablet, sugar-coated tablet, capsule, granule, suspension, liquid, syrup, drop, buccal formulation, suppository or other dosage forms. A particle is produced by pulverizing an active ingredient into a suitable particle size. A powder can be produced by pulverizing an active ingredient into a suitable particle size followed by mixing with a pharmaceutical carrier, such as an edible carbohydrate including starches or mannitol, which has also been pulverized into a suitable particle size. Those which may be added if necessary are flavors, preservatives, dispersing agents, colorants, fragrances and the like.
A capsule may be produced by filling a particle or powder which has previously been pulverized as described above or a granule obtained as described in the section of a tablet for example in a capsule such as a gelatin capsule. It is also possible that an additive such as a lubricant, fluidizing agent, such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol is mixed with the pulverized material prior to the filling procedure. For the purpose of enhancing the availability of a medicament when a capsule is ingested, a disintegrant or solubilizing agent, such as carboxymethyl cellulose, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, sodium croscarmellose, sodium carboxy starch, calcium carbonate or sodium carbonate, may be added.
The finely pulverized powder may be suspended and dispersed in a vegetable oil, polyethylene glycol, glycerin and surfactant, and then encapsulated in a gelatin sheet, thereby obtaining a soft capsule. A tablet is produced by formulating a powder mix, converting into a granule or slug, adding a disintegrant or lubricant and then compacting into a tablet. The powder mix is obtained by mixing an appropriately pulverized material with a diluent or base described above if necessary together with a binder (for example, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol and the like), a dissolution retardant (for example, paraffin, wax, hardened castor oil and the like), a resorption promoter (for example, quaternary salt), or an adsorbent (for example, bentonite, kaolin, calcium diphosphate and the like). The powder mix can be granulated by wetting with a binder such as a syrup, starch glue, gum arabic, cellulose solution or polymer solution and then forcing to pass through a sieve. Instead of the procedure for granulating a powder as described above, another procedure may be employed in which a mix is subjected first to a tablet compacting machine to form a morphologically incomplete slug which is then ground.
A granule thus obtained may contain, as a lubricant, stearic acid, stearates, talc, mineral oil and the like, for the purpose of preventing any adhesion with each other. The mixture thus lubricated is then compacted into tablets.
A plane tablet thus obtained may be film-coated or sugar-coated.
An active ingredient may be mixed with a fluidized inert carrier and then compacted directly into tablets without being subjected to the granulating or slugging process described above. A transparent or semi-transparent protective film in the form of a shellac sealing film, a film of a sugar or polymeric material and a glossy film of a wax may also be employed.
Other oral dosage forms, such as a solution, syrup and elixir can be formulated as a unit dosage form whose certain amount contains a certain amount of a medicament. A syrup is produced by dissolving a compound in a flavored aqueous solution, while an elixir is produced by using a non-toxic alcoholic carrier. A suspension is formulated by dispersing a compound in a non-toxic carrier. Additives such as a solubilizing agent, an emulsifier (for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), a preservative and a flavor (for example, peppermint oil, saccharin) may also be added if necessary.
An oral unit dosage formulation may also be a microcapsule if desired. Such a formulation may be coated or embedded in a polymer or wax to obtain a prolonged activity or sustained release of the active ingredient.
A rectal administration can be accomplished by using a suppository obtained by mixing a compound with a water-soluble or water-insoluble solid having a low melting point such as a polyethylene glycol, cocoa butter, higher esters (for example, myristyl palmitate) as well as a mixture thereof.
Next, the present invention will be described in more detail with reference to a production examples of typical starting materials (Reference Examples), production examples of a compound according to the present invention (Examples), formulation examples and test examples, which is not limited thereto. Noted that an optical rotation was measured at 20xc2x0 C.